Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita.

Abstract

BACKGROUND:

Telomeres represent the tips of linear chromosomes. In human subjects telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by progressive bone marrow failure, accelerated aging, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of bone marrow failure leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation.

OBJECTIVES:

Limited information is available on the cellular and molecular phenotypes of cells from patients with HH. We analyzed fibroblasts and whole blood cells from 5 patients with HH, 3 of them of unknown molecular origin.

METHODS:

Telomere length, cellular senescence rate, telomerase activity, telomeric aberration, and DNA repair pathways were investigated.

RESULTS:

Although patients' cells exhibit dysfunctional telomeres, sharp differences in the telomeric aberrations and telomere lengths were noted among these patients. In some patients the dysfunctional telomere phenotype was unprecedented and associated with either normal telomere length or with telomeric aberrations akin to fragile telomeres. This result is of particular importance because the molecular diagnosis of these patients is primarily based on telomere length, which therefore misses a subset of patients with telomere dysfunction.

CONCLUSION:

These observations provide the notions that (1) various telomere defects can lead to similar clinical features, (2) telomere dysfunction in cells from patients with DC/HH is not always associated with short telomeres, and (3) additional factors, likely involved in telomere protection rather than in length regulation, are responsible for a subset of DC/HH.

• Authors: Fabien Touzot, Laetitia Gaillard, Nadia Vasquez, Tangui Le Guen, Yves Bertrand, Jean Bourhis, Thierry Leblanc, Alain Fischer, Jean Soulier, Jean-Pierre de Villartay, Patrick Revy
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 129 Issue 2 Pg. 473-82, 482.e1-3 (Feb 2012) ISSN: 1097-6825 [Electronic] United States
• PMID: 22078571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Chemical References

• TINF2 protein, human
• Telomere-Binding Proteins
• DNA
• Telomerase

Topics

• Child, Preschool
• DNA (genetics)
• DNA Repair
• Dyskeratosis Congenita (genetics, metabolism, pathology)
• Female
• Fetal Growth Retardation (genetics, metabolism, pathology)
• Fibroblasts (enzymology, metabolism, pathology)
• Humans
• Infant
• Intellectual Disability (genetics, metabolism, pathology)
• Male
• Microcephaly (genetics, metabolism, pathology)
• Phenotype
• Sequence Analysis, DNA
• Telomerase (metabolism)
• Telomere (metabolism, pathology)
• Telomere-Binding Proteins (genetics)